It is known that certain 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines are active in the treatment of CNS disorders, such as psychiatric and neurological disorders, and are also useful as anticonvulsants, for example in the treatment of epilepsy. These triazines are also non-depressant at therapeutic dose levels and are therefore advantageous as compared with depressant anti-epileptics such as phenobarbitone.
A particularly preferred compound of this type is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (e.g. European Patent 21121).
A known process for preparing 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines, comprises reacting substituted benzoyl cyanides with aminoguanidine in aqueous solutions of strong acids such as nitric acid (J. A. Settepani and A. B. Borkovec, J. Heterocycl. Chem., 1966, 3, 188, U.S. Pat. Nos. 3,637,688; 4,486,354; 4,602,017; 4,649,139, R. W. A. Rees et al, J. Med. Chem., 1972, 15, 859; European Patent Nos. 21,121; 142,306; 247,892, Israeli Patent Nos. 60,201; 73,332; 82,710) and sulfuric acid (European Patent No. 247,892, Israeli Patent No. 82,710) to produce amidinohydrazone of the general formula (A): ##STR3##
wherein
R.sub.1 is halogen, C.sub.1-4 alkyl or trifluoromethyl, R.sub.2 is hydrogen, halogen, C.sub.1-4 alkyl or trifluoromethyl, or R.sub.1 and R.sub.2 form a --CH.dbd.CH--CH.dbd.CH-- group optionally substituted by a halogen atom or a C.sub.1-4 alkyl or trifluoromethyl group, R.sub.3 and R.sub.4 are independently selected from hydrogen, halogen, C.sub.1-4 alkyl or trifluoromethyl groups and R.sub.5 is hydrogen, methyl or fluorine. PA1 R.sub.1 -R.sub.5 are as hereinbefore defined) are obtained by ring closure of a compound of the formula A. PA1 R.sub.1 to R.sub.5 are independently selected from hydrogen, halogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-6 alkoxy, all optionally substituted by one or more of halogen, hydroxy and aryl groups, as well as being independently selected from amino, mono- or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups, which process comprises reacting a compound of the general formula (II): ##STR6## PA1 R.sub.1 to R.sub.5 are as defined in formula (I), with aminoguanidine bicarbonate in a mixture of a water-soluble solvent and polyphosphoric acid. PA1 4- Chlorobenzoyl cyanide amidinohydrazone, PA1 2,3-Dichlorobenzoyl cyanide amidinohydrazone, PA1 2,4- Dichlorobenzoyl cyanide amidinohydrazone, PA1 3,4- Dichlorobenzoyl cyanide amidinohydrazone. PA1 R.sub.1 to R.sub.5 are as defined in the formula (I), can be obtained from the compound of the formula (I) by a procedure similar to that described in the literature, i.e. Beyer et al, Chem. Ber. 1960, 93, 2209; J. A. Settepani and A. B. Borkovec, J. Heterocycl. Chem., 1966, 3, 188, U.S. Pat. Nos. 3,637,688; R. W. A. Rees et al, J. Med. Chem., 1972, 15, 859; European Patent Nos, 21,121; 247,892.
3,5-Diamino-6-(substituted phenyl)-1,2,4-triazines (compounds of the general formula (B): ##STR4##
wherein
The ring closure is normally carried out by refluxing in an alcohol, such as methanol, ethanol, 1-propanol and the like, in the presence of a strong base, such as sodium hydroxide, potassium hydroxide and the like.
However, the reaction of substituted benzoyl cyanides with aminoguanidine in the aqueous solutions of strong acids is very slow and usually from 2 to 21 days are required to complete this reaction. On the other hand, substituted benzoyl cyanides are hydrolyzed at the reaction conditions, and overall yield of the triazines is low (from 2 to 41%) (Table).
TABLE Yield of the Temper- compound Compounds ature Time of of the of the Solvent of the of the the formula formula (A) reaction reaction reaction (B) R.sup.6.dbd.R.sup.7.dbd.Cl a) DMSO and 8N 25.degree. C. 7 days 15.6%* R.sup.8.dbd.R.sup.9.dbd.R.sup.10.dbd.H aqueous nitric acid b) Acetonitrile 20-30.degree. C. 48 hours 41%** and 63% aqueous sulfuric acid R.sup.6.dbd.R.sup.7.dbd.R.sup.9.dbd.Cl DMSO and 8N 20-30.degree. C. 21 days 1.6%* R.sup.8.dbd.R.sup.10.dbd.H aqueous nitric acid R.sup.6.dbd.R.sup.8.dbd.Cl DMSO and 8N 25.degree. C. 24 hours 8%*** R.sup.7.dbd.R.sup.9.dbd.R.sup.10.dbd.H aqueous nitric acid R.sup.7.dbd.R.sup.8.dbd.Cl DMSO and 8N 25.degree. C. 24 hours 23%*** R.sup.6.dbd.R.sup.9.dbd.R.sup.10.dbd.H aqueous nitric acid R.sup.8.dbd.Cl DMSO and 8N 25.degree. C. 24 hours 37%*** R.sup.6.dbd.R.sup.7.dbd.R.sup.9.dbd. aqueous nitric R.sup.10.dbd.H acid *U.S. Pat. No. 4,486,354 **European Patent No. 247,892 ***R. W. A. Rees et al, J. Med. Chem., 1972, 15, 859.